Mycobacterium tuberculosis (TB) remains the leading cause of death among persons living with human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) in southern Africa. This syndemic has resulted in an overwhelming burden for healthcare workers and the healthcare system. Drug- resistant TB remains a growing threat to public health despite advances in treatment and diagnosis over the past decade. South Africa has the world highest rate of TB/HIV co-infection and ranks fourth worldwide for multi-drug resistant (MDR) TB incidence and HIV prevalence. Treatment of MDR-TB, defined as resistance to isoniazid and rifampin, remains challenging and complex and success of second line treatment regimens is considerably less likely. Prospective cohort studies from South Africa report less than 50% treatment success (i.e. cure/completion) and marked differences between patients with and without HIV. International and South Africa specific MDR-TB guidelines recommend integration with HIV treatment programs and movement toward community-based programs within the primary care system. Although heralded as a major success by the HIV and TB treatment communities, implementation of TB/HIV integration in a community-based platform is much more challenging, requiring clinicians to navigate both HIV and MDR-TB treatment guidelines, overlapping drug toxicities and parallel care systems potentially leading to greater fragmentation of care. Nurse case management (NCM) models in which a registered nurse coordinates treatment plans to ensure that appropriate and timely care is given have been shown to improve treatment outcomes. There is little evidence to describe NCM of MDR-TB/HIV co-infected patients by registered nurses globally, and specifically MDR- TB/HIV in sub-Saharan Africa. The proposed 5-year interdisciplinary cluster randomized study will determine the impact and cost-effectiveness of a NCM intervention on MDR-TB treatment outcomes in South Africa, the epicenter of the MDR-TB/HIV epidemics. We hypothesize that the NCM intervention sites will report increased cure/completion rates of MDR-TB among patients with and without HIV compared to control sites. Sampling 10 clusters with 300 subjects each (1500 per group), achieves 88% power to detect a difference between the groups of 0.18; a clinically meaningful difference in MDR-TB treatment outcomes. The Chronic Care Model (CCM) identifies essential elements of a health care system that encourage high-quality chronic disease care in a bundled approach. These elements provided the conceptual framework for the proposed NCM intervention, a multi-faceted systems level intervention bundle to improve MDR-TB/HIV treatment outcomes. The proposed study is innovative and significant as it will translate a NCM intervention within the proven CCM framework in a low resource setting with a robust cost-effectiveness analysis. The study is globally relevant as it addresses the essential question of how can the implementation of TB/HIV integration occur in an evidence- based and sustainable manner.